Pathogenesis

Congenital and acute acquired TTP are due to a deficiency of von Willebrand factor cleaving protein, also known as ADAMTS1.^[1] 

Epidemiology

The incidence is rising as there is greater recognition of the condition. It is currently around 3.7 cases per million patients.

• TTP is rare, with a reported incidence of 6 per 1,000,000 per year in the UK.^[1] 
• It is most common in adults, although it has been reported in neonates and nonogenarians. The peak occurs in the fourth decade of life.
• It is more common in females than in males; the ratio is 3:2.

Aetiology

• Pregnancy and the postpartum state account for 10-25% of cases of TTP.^[2] The course of the syndrome is not altered by termination of pregnancy.
• It occurs in greater frequency in patients with HIV infection; it may be the initial presenting syndrome.
• It is often associated with cancer.
• Cancer chemotherapeutic agents associated with TTP include mitomycin C, tamoxifen, bleomycin, and cytosine arabinoside.
• Other drugs suspected of causing TTP include:
  • Immunosuppressive agents - eg. ciclosporin A.
  • Crack cocaine.
  • Oral contraceptives.
  • Penicillin and rifampin.

Toxins associated with TTP include the following:

• Escherichia coli; E. coli O157:H7 is a toxin-producing bacterium.
• Spider and bee venoms.

Presentation

There may be a prodrome resembling a flu-like illness, including fever, fatigue and generalised malaise and arthralgias. A patient can present with:^[1]

• Thrombocytopenia (epistaxis, bruising, petechiae, gingival bleeding, haematuria, menorrhagia, gastrointestinal bleeding, retinal haemorrhage, and haemoptysis.
• Confusion, headache, paresis, aphasia, dysarthria, visual problems, encephalopathy, and coma.
• Fever, pallor, jaundice (haemolytic anaemia), fatigue, arthralgia, and myalgia.
• Proteinuria, micro-haematuria, and raised urea and creatinine.^[2] 
• Chest pain, heart failure, arrhythmias, and hypotension.
• Abdominal pain.

Examination

This may be normal. However, you may find:

• Fever.
• Purpura - non-palpable small purpuric spots or petechiae occur with thrombocytopenia, ie platelet count <50 x 10⁹/L.
  
  
• Jaundice - secondary to haemolysis.
• Severe hypertension.
• Neurological problems as above.
• Splenomegaly.

Investigations

• Blood smear shows fragmented erythrocytes, ie schistocytes. This is consistent with haemolysis. Schistocytes are a hallmark of the disease, but there are no guidelines as to the number of schistocytes required to differentiate TTP from other thrombotic microangiopathies.
• Renal function tests; creatinine level is mildly elevated in about half of patients.
• Coagulation studies are non-diagnostic.
• LDH level is extremely elevated. This is released from ischaemic or necrotic tissue cells.
• Indirect bilirubin level is elevated.
• Reticulocyte count is elevated.
• Urinalysis shows proteinuria and microscopic haematuria.
• Pre-treatment measurement of ADAMTS13 activity levels and anti-ADAMTS13 antibodies.^[1] 
• Serological tests for HIV, hepatitis B virus and hepatitis C virus, autoantibody screen and a pregnancy test (when appropriate) should be performed at presentation.^[1] 

Differential diagnosis^[1] 

• Autoimmune haemolysis/Evans' syndrome.
• Disseminated intravascular coagulation.
• Pregnancy-associated - eg, HELLP syndrome (= haemolysis, elevated liver enzymes and low platelets), eclampsia, haemolytic uraemic syndrome.
• Drugs - eg, quinine, simvastatin, interferon, calcineurin inhibitors.
• Malignant hypertension.
• Infections - typically, viral (cytomegalovirus, adenovirus, herpes simplex virus) or severe bacterial (meningococcus, pneumococcus), fungal.
• Autoimmune disease (lupus nephritis, acute scleroderma).
• Vasculitis.
• Haemolytic uraemic syndrome (diarrhoea positive/negative).
• Malignancy.
• Catastrophic antiphospholipid syndrome.

Management

Intravenous (IV) plasma exchange

IV plasma exchange is also called plasmapheresis. It is the present standard of treatment for TTP. During the plasma exchange, the inhibitory antibodies are removed and the plasma is replenished with the deficient protease.

• Plasma exchange should be initiated as soon as possible, preferably within 4-8 hours.^[1]
• Infusion of fresh frozen plasma (FFP) 30 mL/kg can be used until the patient can be transferred to a facility where plasma exchange is available.
• Glucocorticoid steroid and antiplatelet agents are used. Steroids often are administered prior to plasma exchange. Steroids have no proven added benefit over plasmapheresis alone, but some patients respond to high-dose prednisone (200 mg/day) alone, without plasma therapy.
• Haemorrhage is a concern with antiplatelet therapy and its benefit has not been proven.^[3]
• Rituximab:
  • Recently the use of rituximab, a monoclonal anti-CD20 antibody, has also become mainline treatment.^[4]This has been associated with fewer relapses.
  • In acute idiopathic TTP with neurological or cardiac pathology (associated with a high mortality) rituximab should be considered on admission, in combination with plasma exchange and steroids.^[1] 
  • Patients with refractory or relapsing immune-mediated TTP should be offered rituximab.^[1] 
  • Increased plasma exchange and/or rituximab therapy are the agents of choice in relapsing disease.^[1] 
• Other treatments:^[1] 
  • Red cell transfusion should be administered according to clinical need, especially if there is cardiac involvement.
  • Folate supplementation is required during active haemolysis.
  • Platelet transfusions are contra-indicated in TTP unless there is life-threatening haemorrhage.
  • Thromboprophylaxis with low molecular weight heparin (LMWH) is recommended once platelet count has reached >50 x 10⁹/L.
  • The use of antiplatelet agents in TTP is unproven but low-dose aspirin may be given during platelet recovery (platelet count >50 x 10⁹/L).

Surgery

Splenectomy may be used to treat patients who do not respond to plasma exchange, or who relapse chronically. Some patients benefit from splenectomy.

Other measures

Supportive care for end-organ damage may be required - eg, haemodialysis for renal failure.

Prognosis

Plasma exchange was introduced in the 1960s improving the survival rate from approximately 3% to 80-90%.^[2] Early recognition of the condition with plasma infusion and exchange has improved the outcome.

33% of patients who survive the initial episode, experience a relapse within the next ten years.